US10399953B2 - Preparation of furan fatty acids from 5-(chloromethyl)furfural - Google Patents
Preparation of furan fatty acids from 5-(chloromethyl)furfural Download PDFInfo
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- US10399953B2 US10399953B2 US15/751,809 US201615751809A US10399953B2 US 10399953 B2 US10399953 B2 US 10399953B2 US 201615751809 A US201615751809 A US 201615751809A US 10399953 B2 US10399953 B2 US 10399953B2
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- 0 [1*]CC1=C([2*])C([3*])=C(ccCC)O1 Chemical compound [1*]CC1=C([2*])C([3*])=C(ccCC)O1 0.000 description 23
- QNFOSILJAYKSAF-UHFFFAOYSA-N CCCCCCCCCCCC1=C(C)C(C)=C(CCC)O1 Chemical compound CCCCCCCCCCCC1=C(C)C(C)=C(CCC)O1 QNFOSILJAYKSAF-UHFFFAOYSA-N 0.000 description 5
- XTEXFYLWOKPGFE-UHFFFAOYSA-N CCC1=CC=C(C(C)=O)O1 Chemical compound CCC1=CC=C(C(C)=O)O1 XTEXFYLWOKPGFE-UHFFFAOYSA-N 0.000 description 3
- YFYMBUGFDZCUGU-UHFFFAOYSA-N CCC1=CC=C(C(C)C)O1 Chemical compound CCC1=CC=C(C(C)C)O1 YFYMBUGFDZCUGU-UHFFFAOYSA-N 0.000 description 3
- ZIEHQNOUBYDVDZ-UHFFFAOYSA-N CCCC1=CC=C(CCCCCCCCCCC(=O)O)O1.CCCCCCCCCCCC1=C(C)C(C)=C(CCC)O1 Chemical compound CCCC1=CC=C(CCCCCCCCCCC(=O)O)O1.CCCCCCCCCCCC1=C(C)C(C)=C(CCC)O1 ZIEHQNOUBYDVDZ-UHFFFAOYSA-N 0.000 description 3
- NCEDIRKNBYKMPQ-UHFFFAOYSA-N CCCCCCCCCCCC1=CC=C(CCC)O1 Chemical compound CCCCCCCCCCCC1=CC=C(CCC)O1 NCEDIRKNBYKMPQ-UHFFFAOYSA-N 0.000 description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
Definitions
- value-added products e.g., agrochemicals and healthcare products
- biomass feedstocks e.g., agrochemicals and healthcare products
- business models organized principally around low-margin, high-volume commodities such as biofuels and polymers.
- Atherosclerosis is a chronic inflammatory condition which is the primary cause of cardiovascular diseases that account for about half of the mortalities in developed countries (Lusis (2000) Nature 407: 233). Diets rich in fish and marine organisms are recognized to have an anti-atherosclerotic effect (Calder (2004) Clin. Sci. 107:1; Biscione et al. (2007) Curr. Vasc. Pharmacol. 5: 163; and von Schaky (2007) Curr. Opin. Clin. Nutr. Metab. Care 10:129).
- FFAs rather than omega-3 acids, are responsible for the cardioprotective effects of fish consumption (Glass et al. (1975) Lipids 10: 695).
- Multiple in-vitro antioxidant studies of FFAs have demonstrated that the compounds suppress lipid peroxidation by scavenging radicals and singlet oxygen species (Ishii et al. (1989) Chem. Pharm. Bull. 37: 1396), suggesting applications in the management of hyperlipidemia (Tsuji and Wakimoto (2009) Jpn. Kokai Tokkyo Koho JP2009062315), autoimmune disorders (Tsuji and Wakimoto (2009) Jpn.
- FFAs from marine sources were first isolated and structurally characterized in 1974 (Glass et al (1994) Lipids 9: 1004; and Glass et al. (1975)). All marine FFAs are typified by a long fatty acid chain at the 2-position of the furan ring and a C 3 or C 5 alkyl chain at the 5-position. One or both of the remaining positions of the ring (R 1 , R 2 ) may be substituted with a methyl group. Due to their low natural abundance and sensitivity to isolation procedures, a number of synthetic approaches to these compounds have been reported. Since FFAs are biogenetically derived by the oxidation of lipids (Batna and Spiteller (1991) Liebigs Ann. Chem.
- the present invention surprisingly meets the need for a high-yielding approach to naturally occurring and biologically active FFAs, as well as other needs, by demonstrating the additional synthesis of FFAs from this CMF platform.
- the present invention provides methods of preparing a compound of Formula I having the structure:
- the method includes forming a first reaction mixture including an alcohol and a compound of Formula II:
- X 1 is halogen
- R 4a and R 4b are C 1-18 alkyl.
- the method further includes forming a second reaction mixture including an alkylating agent with a formula R 1 ML n , and a compound of Formula I, under conditions sufficient to form a compound of Formula IV:
- the method further includes forming a third reaction mixture including an aqueous acid and a compound of Formula IV, under conditions sufficient to form a compound of Formula V:
- the method further includes forming a fourth reaction mixture including a phosphonium salt of Formula VI:
- R 5a , R 5b , and R 5c can each independently be H, C 1-18 alkyl, C 2-18 alkenyl, or C 6-12 aryl.
- R 2 and R 3 can each independently be H or C 1-6 alkyl.
- X 2 is halogen
- R 1 is C 1-18 alkyl
- m is an integer from 1 to 18.
- the present invention provides compounds having the structure of Formula I wherein R 1 is C 1-18 alkyl, m is an integer from 1-18, and R 2 and R 3 can each independently be H or C 1-6 alkyl.
- the present invention provides nutritional supplements including a compound having the structure of Formula I wherein R 1 is C 1-18 alkyl, m is an integer from 1-18, and R 2 and R 3 can each independently be H or C 1-6 alkyl.
- FIG. 1 illustrates chemical structures of molecules synthesized using the renewable platform molecule 5-(chloromethyl)furfural as a starting material.
- FIG. 2 is a scheme for the synthesis of furan fatty acids.
- Reagents and conditions include: (a) BuOH, HCl (cat.), 99%; (b) EtMgCl, Ni(acac) 2 , diallyl ether (DAE), THF, ⁇ 30° C.; (c) HCl/H 2 O, 83% over 2 steps; (d) (9-carboxynonyl)triphenylphosphonium iodide, LiHMDS, THF/DMSO; (e) H 2 (balloon), Pd/C, THF, 92% over 2 steps; (f) paraformaldehyde, HBr, AcOH; (g) H 2 (1.2 bar), Pd/C, THF/H 2 O, 80% over 2 steps.
- FIG. 3 is a graph of results from a 2,2-diphenyl-1-picrylhydrazyl assay of the antioxidant activities of 11-(5-propylfuran-2-yl)undecanoic acid and 11-(3,4-dimethyl-5-propylfuran-2-yl)undecanoic acid.
- the present invention provides methods of preparing furan fatty acids (FFAs) from 5-chloromethyl(furfural) (CMF).
- FFAs furan fatty acids
- CMF 5-chloromethyl(furfural)
- the present invention also provides FFA compounds and nutritional supplements including one or more FFA compounds.
- Fatty acid refers to a carboxylic acid having an aliphatic tail, typically from 4 to 30 carbon atoms long. Fatty acids can be saturated, mono-unsaturated or poly-unsaturated. Fatty acids useful in the present invention also include branched fatty acids such as iso-fatty acids.
- fatty acids useful in the present invention include, but are not limited to, butyric acid (C4), caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), palmitoleic acid (C16), stearic acid (C18), isostearic acid (C18), oleic acid (C18), vaccenic acid (C18), linoleic acid (C18), alpha-linoleic acid (C18), gamma-linolenic acid (C18), arachidic acid (C20), gadoleic acid (C20), arachidonic acid (C20), eicosapentaenoic acid (C20), behenic acid (C22), erucic acid (C22), docosahexaenoic acid (C22), lignoceric acid (C24) and hexacosanoic
- Alkyl refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of carbons, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 .
- C 1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
- Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
- Alkenyl refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6 . Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more.
- alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.
- Alkenyl groups can be substituted or unsubstituted.
- Aryl refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings.
- Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
- Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group.
- Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group.
- aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.
- Aryl groups can be substituted or unsubstituted.
- Halogen refers to fluorine, chlorine, bromine and iodine.
- Salt refers to acid or base salts of the compounds used in the methods of the present invention.
- Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
- salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
- bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
- acid addition salts such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
- the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- Metal refers to elements of the periodic table that are metallic and that can be neutral, or negatively or positively charged as a result of having more or fewer electrons in the valence shell than is present for the neutral metallic element.
- Metals useful in the present invention include the alkali metals, alkali earth metals, transition metals and post-transition metals.
- Alkali metals include Li, Na, K, Rb and Cs.
- Alkaline earth metals include Be, Mg, Ca, Sr and Ba.
- Transition metals include Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg and Ac.
- Post-transition metals include Al, Ga, In, TI, Ge, Sn, Pb, Sb, Bi, and Po.
- Rare earth metals include Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
- Acid refers to a compound that is capable of donating a proton (H) under the Bronsted-Lowry definition, or is an electron pair acceptor under the Lewis definition.
- Acids useful in the present invention are Bronsted-Lowry acids that include, but are not limited to, alkanoic acids or carboxylic acids (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acids and mineral acids, as defined herein.
- Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromice acid, etc.), halogen oxoacids (hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid, nitric acid, phosphoric acid, chromic acid and boric acid.
- Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, triflouromethanesulfonic acid, camphorsulfonic acid, among others.
- Alcohol refers to an alkyl group, as defined within, having a hydroxy group attached to a carbon of the chain.
- alcohol includes, but is not limited to, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, pentanol and hexanol, among others.
- Alcohols useful in the present invention are fully saturated. One of skill in the art will appreciate that other alcohols are useful in the present invention.
- Alkylating agent refers to a material that selectively alkylates a starting molecule by adding a desired aliphatic carbon chain to the molecule.
- An alkylating agent can be nucleophilic alkylating agent, an electrophilic alkylating agent, or a carbene.
- alkylating agents include organometallic compounds, and alkyl halides used with a Lewis acid catalyst.
- Ligand refers to an ion or functional group of a molecule that binds to a central metal atom to form a coordination complex.
- a ligand can be, for example, an amine, a phosphine, CO, N 2 , an alkene, or halogen.
- Forming a reaction mixture refers to the process of bringing into contact at least two distinct species such that they mix together and can react, either modifying one of the initial reactants or forming a third, distinct, species, a product. It should be appreciated, however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
- “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject.
- Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
- binders include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
- Nutritional supplement refers to foods or food ingredients that provide to a subject health or medical benefits beyond those associated with the basic caloric value of the food.
- a nutritional supplement can be administered to or taken by a subject to provide, supply, or increase one or more nutrients.
- the one or more nutrients can be, for example, a vitamin, mineral, trace essential element, amino acid, peptide, nucleic acid, oligonucleotide, lipid, cholesterol, steroid, fatty acid, antioxidant, or a carbohydrate.
- Food refers to an edible substance to be ingested orally.
- a food can be, for example, a beverage or a non-beverage.
- a food can be, for example, a sweet, a confectionary, a nutrient, or a pharmaceutical.
- Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
- Edible refers to a substance that can be eaten by animals or humans. The term encompasses substances that are deemed non-toxic and can be orally ingested and tolerated.
- Described here a synthetic route to FFA natural products with the biorefinery platform molecule CMF at their core.
- the approach incorporates sufficient versatility to provide FFAs of different chain lengths on either the 2- or 5-positions of the furan ring, and to produce either unalkylated or dialkylated versions of FFAs.
- the application of bromomethylation in the synthesis also provides functional handles for the production of novel FFA analogues with substituents other than methyl groups in the 3- and 4-positions.
- the present invention provides several methods of preparing FFA compounds having the structure of Formula I:
- R 1 can be C 1-18 alkyl
- R 2 and R 3 can each independently be H or C 1-6 alkyl
- m can be an integer from 1 to 18.
- the methods include forming a first reaction mixture including an alcohol and a compound having the structure of Formula II:
- X 1 is halogen
- R 4a and R 4b can be C 1-18 alkyl.
- the methods further include forming a second reaction mixture including an alkylating agent with a formula R 1 ML n , and a compound having the structure of Formula III, under conditions sufficient to form a compound having the structure of Formula IV:
- M is a metal
- L is a ligand
- n is an integer from 1 to 3.
- the methods further include forming a third reaction mixture including an aqueous acid and a compound of Formula IV, under conditions sufficient to form a compound having the structure of Formula V:
- the methods further include forming a fourth reaction mixture including a phosphonium salt having the structure of Formula VI:
- X 2 is halogen
- R 5a , R 5b , and R 5c can each independently be H, C 1-18 alkyl, C 2-18 alkenyl, or C 6-12 aryl.
- the alcohol of the first reaction mixture can be, for example methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, pentanol or hexanol.
- the alcohol can be propanol, butanol, or pentanol. In some embodiments, the alcohol is butanol.
- R 1 of Formula I can be C 1-18 alkyl. In some embodiments, R 1 is methyl, ethyl, or propyl. In some embodiments, R 1 is ethyl.
- R 2 and R 3 of Formula I can each independently be H or C 1-6 alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is methyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl. In some embodiments, both R 2 and R 3 are H. In some embodiments, both R 2 and R 3 are methyl. Integer m of Formula I can be 1-18. In some embodiments, integer m is 6, 8, or 10. In some embodiments, integer m is 8.
- X 1 of Formula II can be fluorine, chlorine, bromine, or iodine. In some embodiments, X 1 is chlorine.
- R 4a and R 4b of Formula III can be C 1-18 alkyl. In some embodiments, R 4a and R 4b are ethyl, propyl, butyl, or pentyl. In some embodiments R 4a and R 4b are butyl.
- the metal of the alkylating agent can be, for example, magnesium, lithium, copper, or sodium. In some embodiments, the metal of the alkylating agent is magnesium.
- the ligand of the alkylating agent can be halogen. In some embodiments, the ligand of the alkylating agent is chloride.
- Integer n of the alkylating agent formula can be 1, 2, or 3. In some embodiments, integer n is 1. In some embodiments, the alkylating agent has the formula R 1 MgX 3 , wherein X 3 is halogen. In some embodiments, the alkylating agent is ethylmagnesium chloride.
- the aqueous acid of the third reaction mixture can be, for example, perchloric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid. In some embodiments, the aqueous acid of the third reaction mixture is hydrochloric acid.
- R 5a , R 5b , and R 5c of Formula VI can be H.
- R 5a , R 5b , and R 5c of Formula VI can be C 1-18 alkyl.
- R 5a , R 5b , and R 5c of Formula VI can be C 2-18 alkenyl.
- R 5a , R 5b , and R 5c of Formula VI can be C 6-12 aryl. In some embodiments, R 5a , R 5b , and R 5c are each phenyl.
- X 2 of Formula VI can be fluorine, chlorine, bromine, or iodine. In some embodiments, X 2 is iodine.
- the method of preparing FFA compounds further includes forming a fifth reaction mixture including hydrogen, a first hydrogenation catalyst, and the compound of Formula I having the structure:
- the first hydrogenation catalyst can be a homogeneous or heterogeneous catalyst.
- the catalyst can comprise platinum, palladium, rhodium, ruthenium, or nickel.
- the first hydrogenation catalyst is palladium on carbon.
- the method of preparing FFA compounds further includes forming a sixth reaction mixture including formaldehyde or paraformaldehyde, hydrogen bromide, and the compound of Formula I having the structure:
- the method further includes forming a seventh reaction mixture including hydrogen, a second hydrogenation catalyst, and a compound having the structure of Formula VII under conditions sufficient to form the compound of Formula I having the structure:
- the second hydrogenation catalyst can be a homogeneous or heterogeneous catalyst.
- the catalyst can comprise platinum, palladium, rhodium, ruthenium, or nickel. In some embodiments, the second hydrogenation catalyst is palladium on carbon.
- the compound of Formula I has the structure
- the compound of Formula I has the structure
- the compound of Formula I has the structure
- the present invention provides several FFA compounds. In some embodiments, the present invention provides compounds of Formula I having the structure:
- the compound of Formula I has the structure
- the compound of Formula I has the structure
- the compound of Formula I has the structure
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
- Certain specific compounds of the present invention contain basic acidic functionalities that allow the compounds to be converted into base addition salts. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
- the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
- Isomers include compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
- Tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
- the present invention provides compounds, which are in a prodrug form.
- Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
- prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
- the compounds of the invention can be synthesized by a variety of methods known to one of skill in the art (see Comprehensive Organic Transformations Richard C. Larock, 1989) or by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the compounds of the invention are both readily apparent and accessible to those of skill in the relevant art.
- the discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds of the present invention. One of skill in the art will appreciate that other methods of making the compounds are useful in the present invention.
- the compounds of the present invention can be prepared by a variety of methods known to one of skill in the art.
- the methods of making the compounds of the present invention can include any suitable protecting group or protecting group strategy.
- a protecting group refers to a compound that renders a functional group unreactive to a particular set of reaction conditions, but that is then removable in a later synthetic step so as to restore the functional group to its original state.
- Such protecting groups are well known to one of ordinary skill in the art and include compounds that are disclosed in “Protective Groups in Organic Synthesis”, 4th edition, T. W. Greene and P. G M. Wuts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.
- the present invention provides several nutritional supplements including FFA compounds. In some embodiments, the present invention provides nutritional supplements including a compound of Formula I having the structure:
- the compound of Formula I has the structure
- the compound of Formula I has the structure
- the compound of Formula I has the structure
- the nutritional supplement can be, for example, a nutraceutical, a dietary supplement, a food, or a food ingredient.
- the supplement can also serve as a natural food additive to, for example, prevent rancidity in fats
- the nutritional supplement can provide health benefits for a subject suffering from a heart disease, or having risk factors associated with an elevated occurrence or risk of heart disease.
- the heart disease can be, for example, atherosclerosis.
- the health benefits can include, for example, a change in the lipid composition in the blood of the subject.
- the nutritional supplement can comprise any amount of the compounds disclosed herein, but will typically contain an amount determined to supply a subject with a desired dose of one or more furan fatty acids.
- the exact amount of compound required in the nutritional supplement will vary from subject to subject, depending on the species, age, weight, and general condition of the subject, the severity of the dietary deficiency being treated, and the particular mode of administration.
- the nutritional supplement can also comprise one or more other nutrients, such as a vitamin, mineral, trace essential element, amino acid, peptide, nucleic acid, oligonucleotide, lipid, cholesterol, steroid, thiosulfinate, or a carbohydrate.
- the nutritional supplement can also comprise other components such as preservatives, antimicrobials, antioxidants, chelating agents, thickeners, flavorings, diluants, emulsifiers, dispersing aids, or binders.
- the nutritional supplement can further comprise vitamins and minerals including, but not limited to, calcium phosphate or acetate, tribasic; potassium phosphate, dibasic; magnesium sulfate or oxide; salt (sodium chloride); potassium chloride or acetate; ascorbic acid; ferric orthophosphate; niacinamide; zinc sulfate or oxide; calcium pantothenate; copper gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride; thiamin mononitrate; folic acid; biotin; chromium chloride or picolonate; potassium iodide; sodium selenate; sodium molybdate; phylloquinone; vitamin D3; cyanocobalamin; sodium selenite; copper sulfate; vitamin A; vitamin C; inositol; or potassium iodide.
- vitamins and minerals including, but not limited to, calcium phosphate or acetate, tribasic; potassium
- the nutritional supplement can further comprise at least one food flavoring such as acetaldehyde (ethanal), acetoin (acetylmethylcarbinol), anethole (parapropenyl anisole), benzaldehyde (benzoic aldehyde), n-butyric acid (butanoic acid), d- or l-carvone (carvol), ciunamaldehyde (cinnamic aldehyde), citral (2,6-dimethyloctadien-2,6-al-8, geranial, neral), decanal (N-decylaldehyde, capraldehyde, capric aldehyde, caprinaldehyde, aldehyde C-10), ethyl acetate, ethyl butyrate, 3-methyl-3-phenyl glycidic acid ethyl ester (ethyl-methyl-phenyl-glycidate, strawberry al
- the nutritional supplement can further comprise at least one synthetic or natural food coloring, such as annatto extract, astaxanthin, beet powder, ultramarine blue, canthaxanthin, caramel, carotenal, beta carotene, carmine, toasted cottonseed flour, ferrous gluconate, ferrous lactate, grape color extract, grape skin extract, iron oxide, fruit juice, vegetable juice, dried algae meal, tagetes meal, carrot oil, com endosperm oil, paprika, paprika oleoresin, riboflavin, saffron, or turmeric.
- synthetic or natural food coloring such as annatto extract, astaxanthin, beet powder, ultramarine blue, canthaxanthin, caramel, carotenal, beta carotene, carmine, toasted cottonseed flour, ferrous gluconate, ferrous lactate, grape color extract, grape skin extract, iron oxide, fruit juice, vegetable juice, dried algae meal, tagetes meal, carrot oil, com endosperm
- the nutritional supplement can further comprise at least one phytonutrient, such as comprise at soy isoflavonoids, oligomeric proanthcyanidins, indol-3-carbinol, sulforaphone, fibrous ligands, plant phytosterols, ferulic acid, anthocyanocides, triterpenes, conjugated fatty acids such as conjugated linoleic acid and conjugated linolenic acid, polyacetylene, quinones, terpenes, cathechins, gallates, or quercitin.
- phytonutrient such as comprise at soy isoflavonoids, oligomeric proanthcyanidins, indol-3-carbinol, sulforaphone, fibrous ligands, plant phytosterols, ferulic acid, anthocyanocides, triterpenes, conjugated fatty acids such as conjugated linoleic acid and conjugated linolenic acid, poly
- Sources of plant phytonutrients include, but are not limited to, soy lecithin, soy isoflavones, brown rice germ, royal jelly, bee propolis, acerola berry juice powder, Japanese green tea, grape seed extract, grape skin extract, carrot juice, bilberry, flaxseed meal, bee pollen, ginkgo biloba , red clover, burdock root, dandelion, parsley, rose hips, milk thistle, ginger, Siberian ginseng , rosemary, curcumin, garlic, lycopene, grapefruit seed extract, spinach, and broccoli.
- the nutritional supplement can further comprise at least one vitamin, such as vitamin A, thiamin (B1), riboflavin (B2), pyridoxine (B6), cyanocobalamin (B12), biotin, ascorbic acid (vitamin C), retinoic acid (vitamin D), vitamin E, folic acid and other folates, vitamin K, niacin, or pantothenic acid.
- the supplement comprises at least one mineral, such as sodium, potassium, magnesium, calcium, phosphorus, chlorine, iron, zinc, manganese, fluorine, copper, molybdenum, chromium, selenium, or iodine.
- the nutritional supplement comprises a dosage of a plurality of vitamins or minerals in the range of the recommended daily allowance (RDA) as specified by the United States Department of Agriculture.
- RDA recommended daily allowance
- the nutritional supplement is typically prepared in an oral formulation. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion.
- the nutritional supplement can be provided as a powder or liquid suitable for adding by a consumer to a food or beverage.
- the nutritional supplement is administered to a subject in the form of a powder to be mixed into a beverage.
- the nutritional supplement is stirred into a semi-solid food such as a pudding, topping, sauce, puree, cooked cereal, or salad dressing.
- the nutritional supplement can also be in the form of a pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and a compound of the present invention.
- pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa. (“Remington's”).
- the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from 5% or 10% to 70% of the compounds of the present invention.
- Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen.
- disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
- Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage).
- Pharmaceutical preparations of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
- Push-fit capsules can contain the compounds of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
- a filler or binders such as lactose or starches
- lubricants such as talc or magnesium stearate
- stabilizers optionally, stabilizers.
- the compounds of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
- Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a
- the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin.
- preservatives such as ethyl or n-propyl p-hydroxybenzoate
- coloring agents such as a coloring agent
- flavoring agents such as aqueous suspension
- sweetening agents such as sucrose, aspartame or saccharin.
- Formulations can be adjusted for osmolarity.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
- liquid forms include solutions, suspensions, and emulsions.
- These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- Oil suspensions can be formulated by suspending the compounds of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil; in a fish oil or krill oil; in a mineral oil such as liquid paraffin; or in a mixture of these.
- the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
- Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
- the emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.
- the nutritional supplement can be in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the compounds and compositions of the present invention.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- Example structures below are named according to standard IUPAC nomenclature using the CambridgeSoft ChemDraw naming package.
- Ethylmagnesium chloride (2M in THF), Ni(acac) 2 , diallyl ether, lithium bis(trimethylsilyl)amide (LiHMDS, 1M in THF), 10-bromodecanoic acid (95%), palladium on carbon (5 wt % and 10 wt/o), hydrogen bromide (33 wt % in acetic acid) and triphenylphosphine were purchased from Sigma-Aldrich. Paraformaldehyde (96%) was purchased from Lancaster Synthesis. Triethylamine was purchased from EMD. All the reagents and solvents were used as received.
- CMFDBA 6 1.013 g, 3.687 mmol
- Ni(acac) 2 56 mg, 0.22 mmol
- the vessel was evacuated and backfilled with argon, after which dry THF (20 mL) and diallyl ether (0.45 mL, 0.36 g, 3.7 mmol) were added. The mixture was stirred for 5 min and then cooled to ⁇ 30° C. Ethyl magnesium chloride (2M in THF, 3.70 mL, 7.40 mmol) was added dropwise and the resulting yellow solution was stirred at ⁇ 30° C. for 1 h.
- the antioxidant activity of the FFAs has been evaluated by a range of methods, including spin trapping of N-oxide radicals (Okada et al. (1996) Biol. Pharm. Bull. 19: 1607), inhibition of radically initiated oxygen uptake in linoleic acid (Okada et al. (1990) J. Am. Oil Chem. Soc. 67: 858) and unsaturated fatty acid moieties of phosphatidyl choline liposomes (Ishii et al. (1989) Chem. Pharm. Bull. 37: 1396), and acting as a substrate for plant lipoxygenase (Batna and Spiteller (1994) Lipids 29: 397).
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Abstract
Description
The method includes forming a first reaction mixture including an alcohol and a compound of Formula II:
X1 is halogen, and R4a and R4b are C1-18 alkyl. The method further includes forming a second reaction mixture including an alkylating agent with a formula R1MLn, and a compound of Formula I, under conditions sufficient to form a compound of Formula IV:
M is a metal, L is a ligand, and n is an integer from 1 to 3. The method further includes forming a third reaction mixture including an aqueous acid and a compound of Formula IV, under conditions sufficient to form a compound of Formula V:
The method further includes forming a fourth reaction mixture including a phosphonium salt of Formula VI:
and a compound of Formula V, under conditions sufficient to form the compound of Formula I. R5a, R5b, and R5c can each independently be H, C1-18 alkyl, C2-18 alkenyl, or C6-12 aryl. R2 and R3 can each independently be H or C1-6 alkyl. X2 is halogen, R1 is C1-18 alkyl, and m is an integer from 1 to 18.
R1 can be C1-18 alkyl, R2 and R3 can each independently be H or C1-6 alkyl, and m can be an integer from 1 to 18. The methods include forming a first reaction mixture including an alcohol and a compound having the structure of Formula II:
X1 is halogen, and R4a and R4b can be C1-18 alkyl. The methods further include forming a second reaction mixture including an alkylating agent with a formula R1MLn, and a compound having the structure of Formula III, under conditions sufficient to form a compound having the structure of Formula IV:
M is a metal, L is a ligand, and n is an integer from 1 to 3. The methods further include forming a third reaction mixture including an aqueous acid and a compound of Formula IV, under conditions sufficient to form a compound having the structure of Formula V:
The methods further include forming a fourth reaction mixture including a phosphonium salt having the structure of Formula VI:
and a compound having the structure of Formula V, under conditions sufficient to form the compound having the structure of Formula I. X2 is halogen, and R5a, R5b, and R5c can each independently be H, C1-18 alkyl, C2-18 alkenyl, or C6-12 aryl.
The method further includes forming a seventh reaction mixture including hydrogen, a second hydrogenation catalyst, and a compound having the structure of Formula VII under conditions sufficient to form the compound of Formula I having the structure:
TABLE 1 |
Radical scavenging abilities of furan fatty acids by DPPH assay |
DPPH | |||
| Scavenging % | ||
5a (25 μg/mL) | 4 | ||
5a (50 μg/mL) | −2 | ||
5a (100 μg/mL) | −3 | ||
5b (25 μg/mL) | 7 | ||
5b (50 μg/mL) | 27 | ||
5b (100 μg/mL) | 53 | ||
BHT (100 μg/mL) | 93 | ||
Claims (12)
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US15/751,809 US10399953B2 (en) | 2015-09-14 | 2016-09-14 | Preparation of furan fatty acids from 5-(chloromethyl)furfural |
PCT/US2016/051765 WO2017048864A1 (en) | 2015-09-14 | 2016-09-14 | Preparation of furan fatty acids from 5-(chloromethyl)furfural |
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EP4385508A1 (en) | 2022-12-16 | 2024-06-19 | Centre de Coopération Internationale en Recherche Agronomique pour le Développement (CIRAD) | Furan fatty acids for enhancing muscle mass |
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Cited By (2)
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EP4385508A1 (en) | 2022-12-16 | 2024-06-19 | Centre de Coopération Internationale en Recherche Agronomique pour le Développement (CIRAD) | Furan fatty acids for enhancing muscle mass |
WO2024126642A1 (en) | 2022-12-16 | 2024-06-20 | Centre De Cooperation Internationale En Recherche Agronomique Pour Le Developpement (Cirad) | Furan fatty acids for enhancing muscle mass |
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EP3350146A4 (en) | 2019-03-06 |
US20180230118A1 (en) | 2018-08-16 |
EP3350146A1 (en) | 2018-07-25 |
WO2017048864A1 (en) | 2017-03-23 |
CA2995854A1 (en) | 2017-03-23 |
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